Radiopharmaceutical for diagnostic imaging containing a technetium-99m nitride heterocomplex

ABSTRACT

A radiopharmaceutical for diagnostic imaging containing as an active ingredient a technetium-99m nitride heterocomplex comprising technetium-99m nitride and two different ligands coordinated therewith, i.e., a bisphosphinoamine compound as a π electron acceptor and a bidentate ligand as a π electron donor and represented by the following formula (I): [ 99m Tc(N)(PNP)(XY)] +  (I)wherein  99m Tc(N) is technetium-99m nitride, PNP is a bisphosphinoamine compound and XY is a bidentate ligand, is markedly accumulated in heart and adrenal glands and hence is useful for radiodiagnostic imaging of heart and adrenal glands.

TECHNICAL FIELD

The present invention relates to a radiopharmaceutical for diagnosticimaging containing a technetium-99m nitride heterocomplex as an activeingredient. More particularly, the present invention relates to aradiopharmaceutical for diagnostic imaging which contains as an activeingredient a technetium-99m nitride heterocomplex comprisingtechnetium-99m nitride and two different ligands coordinated therewith,i.e., a diphosphine compound as a π eletron acceptor and a bidentateligand as a π electron donor, and is suitable especially forradiodiagnostic imaging of heart and adrenal glands.

BACKGROUND ART

Of radioactive transition metals used in radiopharmaceuticals, Tc-99m isa nuclide most often used in the field of radiodiagnostic imagingbecause it is advantageous, for example, in that since the energy ofγ-rays emitted by Tc-99m is 141 keV and the half-life of Tc-99m is 6hours, Tc-99m is suitable for imaging, and that Tc-99m can easily beobtained by means of a ⁹⁹Mo—^(99m)Tc generator. It is considered that ifa physiologically active substance or the like can be attached to thisnuclide without impairing the activity, the resulting compound is usefulas a diagnostic agent or a therapeutic agent.

The attempts described below were made to achieve such attachment.Transition metal nitride complexes are excellent in stability tohydrolysis. Therefore, when a transition metal nitride complex issubjected to exchange reaction with any of various ligands having auseful physiological activity, when used in a pharmaceutical, thenitride group of the nitride complex can remain bonded strongly to themetal atom. Accordingly, technetium nitride complexes having varioussubstituents have been proposed. For example, WO 90/06137 disclosesdiethyl bisdithiocarbamate-Tc nitride complex, dimethylbisdithiocarbamate-Tc nitride complex, di-n-propyl bisdithiocarbamate-Tcnitride complex, N-ethyl-N-(2-ethoxyethyl) bisdithiocarbamate-Tc nitridecomplex, etc. In addition, WO 89/08657, WO 92/00982, WO 93/01839 and thelike disclose processes for producing a technetium nitride complex whichcomprises reacting a polyphosphine or the like as a reducing agent fortechnetium with technetium oxide, then reacting a nitride of a metal orammonium as a nitrogen source for nitride with the reaction product toconvert it to the corresponding nitride, and then coordinating aphysiologically active monoclonal antibody or the like with thisnitride.

In these processes, the choice of the physiologically active ligand isso important that it determines properties of the resultingpharmaceutical. But, the metal nitride complex can have various numbersof coordination positions from monodentate to tetradentate and hence isformed in plural forms. Therefore, it has been difficult to obtain asingle complex stoichiometrically having a specific physiologicallyactive ligand.

WO 98/27100 discloses that when a disphosphine compound is coordinatedat two of the four coordination positions of technetium-99m nitride anda bidentate ligand having an electron-donating atom pair is coordinatedat the remaining two coordination positions, the bidentate ligand isstoichiometrically coordinated, so that a single technetium-99m nitrideheterocomplex can be stably obtained. However, no technetium-99m nitrideheterocomplex formed by coordination of a specific bidentate ligandhaving a useful physiological activity has yet been obtained.Furthermore, no technetium-99m nitride heterocomplex has yet beenobtained which is accumulated in specific organs, in particular, heartand adrenal glands and is accumulated in these organs in a higherproportion than in other organs, resulting in a clear distinctionbetween an image obtained and a background.

DISCLOSURE OF INVENTION

In view of such conditions, the present invention is intended to providea radiopharmaceutical for diagnostic imaging comprising a technetium-99mnitride heterocomplex which is markedly accumulated in specific organs,in particular, heart and adrenal glands and hence is useful forradiodiagnostic imaging.

That is, the present invention is a radiopharmaceutical for diagnosticimaging comprising as an active ingredient a technetium-99m nitrideheterocomplex comprising technetium-99m nitride and two differentligands coordinated therewith, i.e., a diphosphine compound as a πelectron acceptor and a bidentate ligand as a π eletron donor andrepresented by the following formula (1):[^(99m)Tc(N) (PNP) (XY)]⁺  (1)wherein ^(99m)Tc(N) is technetium-99m nitride, PNP is abisphosphinoamine compound and XY is a bidentate ligand.

Said bisphosphinoamine compound is preferably a compound represented bythe following formula (2):

wherein R¹ is an alkyl group, a phenyl group or a group represented bythe following formula (3):—(CH₂)₁O(CH₂)₁′CH₃  (3)wherein 1 is an integer in a range of 1≦1≦4 and 1′ is an integer in arange of 0≦1′≦3; and R² is a hydrogen atom, an alkyl group, asubstituted alkyl group, an aryl group, a substituted aryl group, anamino group, an amino acid chain, a biologically active group, a grouprepresented by the formula (3) as defined above or a group representedby —C(═O)R′ wherein R′ is a hydrogen atom, an alkyl group, a substitutedalkyl group, an aryl group, a substituted aryl group, an amino group, anamino acid chain or a biologically active group.

Said bidentate ligand is preferably dithiocarbamic acid, a derivativethereoff, dithiocarbazic acid or derivative thereof, which isrepresented by the following formula (4):

wherein R³is a hydrogen atom, alkaline metal, a positive monocation orthe corresponding salt, and alkyl group, and R⁴ and R⁵are independentlya hydrogen atom, amino group, alkyl group, substituted alkyl group,branched alkyl group or alkoxy group, 2-aminoethanethiol, derivativesthereof, which are represented by the following formula (5):

wherein R⁶ and R⁷ are independently a hydrogen atom, an alkyl group oran aryl group, and 2-aminopropanethiol, derivatives thereof, which arerepresented by the following formula (6):

wherein R⁸, R⁹, R¹⁰ are independently a hydrogen atom, an alkyl group oran aryl group.

In the above formula (4) , R³is preferably a hydrogen atom, an alkylgroup, an alkaline metal, a positive monocation or the correspondingsalt, R⁴ and R⁵ are independently an alkyl group of 1 to 9 carbon atoms,a substituted alkyl group which are represented by the following formula(7), (8), (9) or (10):—(CH₂)_(m)O(CH₂)_(m′)CH₃  (7)wherein m is an integer in a range of 1≦m≦8 and m′ is an integer in arange of 0≦m′≦8,

wherein R¹¹, R¹² are independently an alkyl group or an aryl group,

wherein R¹³ is an alkyl group or an aryl group, n and n′ areindependently an integer in a range of 0≦n≦4, 0≦n′≦4,

wherein n and n′ are independently an integer in a range of 0≦n≦4,0≦n′≦4.

BEST MODE FOR CARRYING OUT THE INVENTION

The technetium-99m nitride heterocomplex according to the presentinvention, i.e., the technetium-99m nitride heterocomplex comprisingtechnetium-99m nitride and two different ligands coordinated therewith,i.e., a bisphosphinoamine compound as a π eletron acceptor and abidentate ligand as a π electron donor can be represented by thefollowing formula (1):[^(99m)Tc(N) (PNP) (XY)]⁺  (1)wherein ^(99m)Tc(N) is technetium-99m nitride, PNP is abisphosphinoamine compound as a π electron acceptor and XY is abidentate ligand as a π electron donor. In the formation process of thetechnetium-99m nitride heterocomplex, a fragment [^(99m)Tc(N) (PNP)]²⁺formed by coordination of the bisphosphinoamine compound (hereinafterproperly abbreviated as PNP) has a high electrophilicity, and thebidentate ligand XY is coordinated with this fragment selectively andquantitatively to form the monocationic asymmetric technetium-99mnitride heterocomplex [^(99m)Tc(N) (PNP) (XY)]⁺.

In general, a diphosphine compound, a π electron acceptor is used as oneof the two different ligands of the technetium-99m nitride heterocomplexof the above formula (1). In the present invention, the diphosphinecompound is preferably a compound of the above formula (2). Thebidentate ligand XY is preferably dithiocarbamic acid, dithiocarbazicacid, or a derivative thereof, which are represented by the aboveformula (4), 2-aminoethnethiol or a derivative thereof which representedby the above formula (5), 3-aminopropanethiol or a derivative thereofwhich represented by the above formula (6).

Dithiocarbamic acid, dithiocarbazic acid, or a derivative thereof has asulfur atom pair [S, S] as an electron-donating atom pair, also2-aminoethnethiol or a derivative thereof or 3-aminopropanethiol or aderivative thereof has an electron-donating atom pair [N, H]. Thetechnetium-99m nitride heterocomplex formed by coordination of such twodifferent ligands PNP and XY is stable monocationic complex having ahigh fat-solubility (see Table 1 given hereinafter). Such complex isstable for imaging organs, in particular, heart and adrenal glandsbecause it is accumlated in specific organs, in particular, heart andadrenal glands and is ahese accumulated in these organs in a higherproportion than other organs, rsulting in a clear ditribution between animage obtained anda background.

Specific examples of the bisphosphinoamine compound PNP of the aboveformula (2) are bis(diphenylphosphinoethyl)amine,bis(diphenylphosphinoethyl)ethylamine,bis(diphenylphosphinoethyl)propylamine,bis(diphenylphosphinoethyl)methoxyethylamine,bis(diphenylphosphinoethyl)butylamine,bis(diphenylphosphinoethyl)acetonylamine,bis(dimethoxyphosphinoethyl)amine,bis(dimethoxyphosphinoethyl)methylamine,bis(dimethoxyphosphinoethyl)ethylamine,bis(dimethoxyphosphinoethyl)propylamine,bis(dimethoxypropylphosphinoethyl)ethylamine,bis(dimethoxypropylphosphinoethyl)propylamine,bis(dimethoxypropylphosphinoethyl)methoxyethylamine,bis(dimethoxypropylphosphinoethyl)ethoxyethylamine,bis(diethoxypropylphosphinoethyl)ethoxyethylamine,bis(diethoxyethylphosphinoethyl)ethylamine,bis(diethoxyethylphosphinoethyl)propylamine,bis(diethoxyethylphosphinoethyl)methoxyethylamine,bis(dimethylphosphinoethyl)methylamine,bis(dipropoxymethylphosphinoethyl)ethoxyethylamine, etc.

There are preferably usedbis(dimethoxypropylphosphinoethyl)methoxyethylamine,bis(diethoxyethylphosphinoethyl)ethylamine,bis(diethoxyethylphosphinoethyl)propylamine,bis(dimethoxypropylphosphinoethyl)ethoxyethylamine,bis(diethoxypropylphosphinoethyl)ethoxyethylamine,bis(diethoxyethylphosphinoethyl)methoxyethylamine,bis(dimethylphosphinoethyl)methylamine,bis(dipropoxymethylphosphinoethyl)ethoxyethylamine, etc.Bis(dimethoxypropylphosphinoethyl)methoxyethylamine,bis(dimethoxylpropylphosphinoethyl)ethoxyethylamine andbis(diethoxypropylphosphinoethyl)ethoxyethylamine are especiallypreferable.

Preferable specific examples of the bidentate ligand XY of the aboveformula (4) are N-methyl-S-methyl dithiocarbazate, N-dimethyldithiocarbamate, N-diethyl dithiocarbamate, N-dipropyl dithiocarbamate,N-methoxy-N-methyl dithiocarbamate, N-methoxyethyl-N-ethyldithiocarbamate, N-methoxypropyl-N-ethyl dithiocarbamate,N-methoxyethyl-N-butyl dithiocarbamate, N-dimethoxyethyldithiocarbamate, N-diethoxyethyl dithiocarbamate, N-diethoxypropyldithiocarbamate, N-diethoxybutyl dithiocarbamate, N-dipropoxyethyldithiocarbamate, N-dibutoxyethyl dithiocarbamate, N-dimethoxypropyldithiocarbamate, N-dimethoxyisopropyl dithiocarbamate, N-ethoxy-N-ethyldithiocarbamate, N-ethoxypropyl-N-propyl dithiocarbamate,N-methoxyethyl-N-isopropyl dithiocarbamate, N-ethoxyethyl-N-propyldithiocarbamate, N-ethoxyethyl-N-ethyl dithiocarbamate,N-propoxy-N-ethyl dithiocarbamate, etc. Of these, especially preferableare N-dimethyl dithiocarbamate, N-diethyl dithiocarbamate, N-dipropyldithiocarbamate, N-methoxy-N-methyl dithiocarbamate, N-ethoxy-N-ethyldithiocarbamate, N-methoxyethyl-N-ethyl dithiocarbamate,N-ethoxyethyl-N-isopropyl dithiocarbamate, N-ethoxyethyl-N-ethyldithiocarbamate, N-methoxypropyl-N-ethyl dithiocarbamate,N-dimethoxyethyl dithiocarbamate and N-diethoxyethyl dithiocarbamate.

In the present invention, the radiopharmaceutical for diagnostic imagingis especially preferably one in which the bisphosphinoamine compound PNPis selected from the group consisting ofbis(dimethoxypropylphosphinoethyl)methoxyethylamine,bis(dimethoxypropylphosphinoethyl)ethoxyethylamine andbis(diethoxypropylphosphinoethyl)ethoxyethylamine, and the bidentateligand XY is selected from the group consisting of N-dimethyldithiocarbamate, N-diethyl dithiocarbamate, N-dipropyl dithiocarbamate,N-methoxy-N-methyl dithiocarbamate, N-ethoxy-N-ethyl dithiocarbamate,N-methoxyethyl-N-ethyl dithiocarbamate, N-ethoxyethyl-N-isopropyldithiocarbamate, N-ethoxyethyl-N-ethyl dithiocarbamate,N-methoxypropyl-N-ethyl dithiocarbamate, N-dimethoxyethyldithiocarbamate and N-diethoxyethyl dithiocarbamate.

Tables 3 to 18 given hereinafter show the biodistribution in rats ofeach of technetium-99m nitride heterocomplexes obtained by usingbis(dimethoxypropylphosphinoethyl)methoxyethylamine (PNP3),bis(dimethoxypropylphosphinoethyl)-ethoxyethylamine (PNP5) orbis(diethoxypropyl-phosphinoethyl)ethoxyethylamine (PNP6) as thebisphosphinoamine compound PNP and each of various bidentate ligands asthe bidentate ligand XY. Tables 19 and 20 show, for comparison, data onthe biodistribution in rats of each of a technetium-99m complex ofhexakis(2-methoxyisobutylisonitrile) (hereinafter abbreviated as(^(99m)Tc) (MIBI)) and a technetium-99m complex ofbis[bis(2-ethoxyethyl)phosphino]ethane-(tetrofosmin) (hereinafterabbreviated as (^(99m)Tc) (Tf)) which are technetium-99m complexesdifferent in kind from those according to the present invention. Tables21 to 23 given hereinafter show data showing the variations with time ofheart accumulation, heart/lung ratios and heart/liver ratios for thecomplexes described above. As can be seen from the data, thetechnetium-99m nitride heterocomplexes according to the presentinvention are markedly accumulated in heart and adrenal glands and theirclearance from lungs and liver is rapid, so that high heart/lung andheart/liver ratios are attained. Thus, the technetium-99m nitrideheterocomplexes according to the present invention have been proved tobe useful for radiodiagnostic imaging of heart and adrenal glands.

The technetium-99m nitride heterocomplex according to the presentinvention can be formulated into a radiopharmaceutical for diagnosticimaging by its aseptic mixing with pharmaceutically acceptableadditives, for example, stabilizers such as ascorbic acid andp-aminobenzoic acid; pH adjusters such as sodium carbonate buffer andsodium phosphate buffer; solubilizers such as α, β, γ-cyclodextrins,meglumine; and excipients such as D-mannitol. In addition, theradiopharmaceutical for diagnostic imaging of the present invention canbe provided in the form of a kit for preparation at the time of usewhich is obtained by combining the technetium-99m nitride heterocomplexwith the above additives.

The radiopharmaceutical for diagnostic imaging of the present inventioncan be administered by a conventional parenteral means such asintravenous administration, and the dosage thereof is determineddepending on a radioactivity level at which imaging is consideredpossible, in view of the age and body weight of a patient, the conditionof a disease to be cured, a radioactive imaging apparatus to be used,etc. When a radiopharmaceutical for diagnostic imaging obtained by usinga substance labeled with technetium-99m is administered to a humanbeing, the dosage thereof is 37 MBq to 1,850 MBq, preferably 185 MBq to740 MBq, in terms of the radioactivity of technetium-99m. Theradio-pharmaceutical for diagnostic imaging of the present invention hadno acute toxicity so long as it was used in the dosage described above.

The technetium-99m nitride heterocomplex according to the presentinvention can easily be obtained by using a kit comprising componentsnecessary for forming said complex. For example, there are prepared avial 1 containing a nitrogen donor, a reducing agent, a stabilizer and apH adjuster, and a vial 2 containing two different ligands, i.e., abisphosphinoamine compound PNP and a bidentate ligand XY, and a solventfor PNP. Then, Na[^(99m)TcO₄] eluted from a ⁹⁹Mo—^(99m)Tc generator isplaced in the vial 1. On the other hand, physiological saline is placedin the vial 2 to dissolve the contents sufficiently, and a definiteamount of the resulting solution is placed in the vial 1, followed byheating at about 100° C., whereby the technetium-99m nitrideheterocomplex can be obtained.

The nitride nitrogen donor is a component necessary for formingtechnetium-99m nitride, and dithiocarbazic acid, dithiocarbazic acidderivatives, hydrazine, hydrazine derivatives, hydrazide derivatives,etc. are used as the nitrogen donor. As the reducing agent, stannouschloride, sodium hydrogensulfite and sodium borohydride, tertiaryphosphines and tris-(m-sulfonatophenyl)phosphine etc. are used. As thestabilizer, ethylenediaminetetraacetic acid (EDTA) is preferable. As thepH adjuster, sodium phosphate buffer and sodium carbonate buffer aresuitably used. Although depending on the ligand PNP, as a solubilizerfor the ligand PNP and a surfactant to prevent attachment of thelipophilic Te-99m-nitride heterocomplex to the rubber and syringe walls,γ-cyclodextrin is suitably used.

Although the contents of each vial may be supplied in the form of asolution, their freeze-drying facilitates their storage and use.

The present invention is illustrated below in further detail withexamples, but the present invention is not limited to the examples.Reagents, analytical methods and the like used in common in thefollowing examples are described below together with theirabbreviations.

-   (1) Bisphosphinoamine compound (PNP):    -   PNP3; bis(dimethoxypropylphosphinoethyl)methoxyethyl-amine (R¹=a        methoxypropyl group and R²=a methoxyethyl group in the formula        (1))    -   PNP5; bis(dimethoxypropylphosphinoethyl)ethoxyethyl-amine (R¹=a        methoxypropyl group and R²=an ethoxyethyl group in the formula        (1))    -   PNP6; bis(diethoxypropylphosphinoethyl)-ethoxyethoxylamine        (R¹=an ethoxypropyl group and R²=an ethoxyethyl group in the        formula (1))-   (2) Physiologically active bidentate ligands (XY):    -   DTC; N-methyl-S-methyl dithiocarbazate    -   DMDC; N-dimethyl dithiocarbamate    -   DEDC; N-diethyl dithiocarbamate    -   DPDC; N-dipropyl dithiocarbamate    -   NOME; N-methoxy-N-methyl dithiocarbamate    -   NOET; N-ethoxy-N-ethyl dithiocarbamate    -   PROME; N-methoxypropyl-N-ethyl dithiocarbamate    -   ISOET; N-ethoxyethyl-N-isopropyl dithiocarbamate    -   BOET; N-ethoxyethyl-N-ethyl dithiocarbamate    -   POET; N-methoxyethyl-N-ethyl dithiocarbamate    -   DPODC; N-dimethoxyethyl dithiocarbamate    -   DBODC; N-diethoxyethyl dithiocarbamate-   (3) Reagents used for synthesizing complexes:    -   SDH; succinic acid dihydrazide    -   EDTA; ethylenediaminetetraacetic acid-   (4) Technetium-99m nitride heterocomplex:

Abbreviated as [^(99m)Tc(N) (PNP3) (XY)]⁺ [^(99m)Tc(N) (PNP5) (XY)]⁺,[^(99m)Tc(N) (PNP6) (XY)]⁺ or ^(99m)Tc(N) heterocomplex.

-   (5) Chromatographic analyses

^(99m)Tc(N) heterocomplexes subjected to experiments were analyzed bythin layer chromatography (TLC) and high performance liquidchromatography (HPLC). Conditions of each chromatography are as follows:

TLC:

Cyclone Instrument (mfd. by Packard) equipped with a phosphor imagingscreen for measuring apparatus and SiO₂-C18 stationary phase plates wasused.

HPLC:

Beckman System Gold apparatus (mfd. by Beckman) equipped with a SolventModule 126, a scanning detector Module 166, a radioisotope detectorModule 170, a reversed-phase C18 precolumn (Ultrasphere Beckman, 4.6×45mm), a reversed-phase C18 column (Ultrasphere Beckman, 4.6×250 mm), anda 100-μL sample loop was used.

-   (6) Purification of complexes

The ^(99m)Tc(N) heterocomplexes were purified as follows in order toremove the influences of impurities, before being used in analysis andbiological evaluation.

A cation exchange resin Sep-Pak cartridge (mfd. by Waters Millipore) wasactivated with 10.0 mL of deionized water. Then, a solution containingeach ^(99m)Tc(N) heterocomplex was diluted with 8 mL of deionized waterand passed through the cartridge. Onto the cartridge, 50 to 90% of theinitial radioactivity was retained. After washing the cartridge withwater and ethanol, the ^(99m)Tc(N) heterocomplex was recovered bypassing ethanol/water (90/10) containing n-Bu₄NBr (0.1 M).

EXAMPLE 1 Synthesis of ^(99m)Tc(N) Heterocomplexes

^(99m)Tc(N) heterocomplexes were synthesized by the following threemethods. The ^(99m)Tc(N) heterocomplexes could be similarly obtained byany of the methods and all of them had a radiochemical purity of 90 to98% as determined by TLC.

Method 1:

0.250 mL of Na[^(99m)TcO₄] (50.0 MBq to 3.0 GBq) eluted from a⁹⁹Mo—^(99m)Tc generator was placed in a vial containing 5 mg of SDH, 5mg of EDTA, SnCl₂ (suspended in 0.1 mL of physiological saline) and 1 mLof ethanol. After the vial was kept at room temperature for 30 min. asolution of 1 mg of PNP3, PNP5 or PNP6 in 0.250 mL of ethanol was addedthereto and the vial was heated at 100° C. for 15 minutes. A solution of1.0 mg of each predetermined bidentate ligand in 0.1 mL of physiologicalsaline was added thereto and then the vial was heated at 100° C. for 15minutes. Thus, monocationic ^(99m)Tc(N) heterocomplexes were obtained.The radiochemical purity of these complexes was 94 to 98% as determinedby TLC.

Method 2:

0.250 mL of Na[^(99m)TcO₄] (50.0 MBq to 3.0 GBq) eluted from a⁹⁹Mo—^(99m)Tc generator was placed in a vial containing 5 mg of SDH, 5mg of EDTA, SnCl₂ (suspended in 0.1 mL of physiological saline) and 1 mLof ethanol.

After the vial was kept at room temperature for 30 minutes, a solutionof 1.0 mg of each predetermined bidentate ligand in 0.1 mL ofphysiological saline was added thereto and then the vial was allowed tostand for 30 minutes. A solution of 1 mg of PNP3, PNP5 or PNP6 in 0.250mL of ethanol was added to the vial, and the vial was heated at 100° C.for 15 minutes. Thus, monocationic ^(99m)Tc(N) heterocomplexes wereobtained. The radiochemical purity of these complexes was 93 to 98% asdetermined by TLC.

Method 3:

0.250 mL of Na[^(99m)TcO₄] (50.0 MBq to 3.0 GBq) eluted from a⁹⁹Mo—^(99m)Tc generator was placed in a vial containing 5 mg of SDH, 5mg of EDTA, SnCl₂ (suspended in 0.1 mL of physiological saline) and 1 mLof ethanol. After the vial was kept at room temperature for 30 minutes,a solution of 1.0 mg of each predetermined bidentate ligand in 0.1 mL ofphysiological saline and a solution of 1 mg of PNP3, PNP5 or PNP6 in0.250 mL of ethanol was added thereto, followed by heating at 100° C.for 15 minutes. Thus, monocationic ^(99m)Tc(N) heterocomplexes wereobtained. The radiochemical purity of these complexes was 90 to 95% asdetermined by TLC.

^(99m)Tc(N) heterocomplexes were synthesized by the above method 1 byusing PNP3, PNP5 or PNP6 as a bisphosphinoamine compound and DTC, DMDC,DEDC, DPDC, NOME, NOET, PROME, ISOET, BOET, POET, DPODC or DBODCbidentate ligand, and were used in the following examples.

EXAMPLE 2 Measurement of Log k′ (Partition Ratio)

For the various ^(99m)Tc(N) heterocomplexes synthesized using PNP3 as abisphosphinoamine compound in Example 1, Log k′ values were determinedat various compositions of a mobile phase for HPLC. As the mobile phase,mixtures of methanol and phosphate buffer (0.02M, pH=7.4) were used at aflow rate of 1.0 mL/min. For each sample, the retention time wasmeasured at a minimum of three different methanol concentrations in themobile phase. The Log k′ values at 0% organic solvent (Log k′₀) wereextrapolated from the linear part of the curve Log k′=a+bC, where C isthe methanol concentration, and Log k′ is Log (tR-to)/to wherein tR isHPLC retension time (min). The column void time (t₀) was regarded asbeing equal to the elution time of pertechnetic acid.

For the ^(99m)Tc(N) heterocomplex of DTC, partition coefficient Log Pwas determined. The HPLC conditions were as follows; A: CH₃COONH₄ (0.01M, pH=5) 10%, B: CH₃CN (THF 0.1%) 90%, C18, 0.5 mL/min. The measurementresults are shown in Table 1.

EXAMPLE 3 Experiment for Confirming the Stability of the ^(99m)Tc(NHeterocomplexes

The stability of the ^(99m)Tc(N) heterocomplexes obtained using PNP3 asa bisphosphinoamine compound in Example 1 was confirmed by ligandexchange reaction with cysteine or glutathione.

250.0 μL of phosphate buffer solution (0.20 M, pH=7.4), 100 μL of waterand 100 μL of each of the ^(99m)Tc(N) heterocomplexes purified weremixed with 50 μL of each of cysteine solutions having differentconcentrations of 10 mM and 1.0 mM, and the resulting mixture was placedin a polypropylene test tube and incubated in a thermostat at 37° C. Ablank solution was obtained by mixing an equal volume of water withoutaddition of cysteine. Aliquots of the resulting solutions were withdrawnat 15 min, 30 min, 60 min and 2 hours after the start of the incubation,and analyzed by TLC. The same experiment as above was carried out exceptfor using glutathione in place of cysteine. All the ^(99m)Tc(N)heterocomplex samples were found stable against transchelation bycystein or glutathione. The experimental results are shown in Table 1.

TABLE 1 Log P or Log k′ and stability of ^(99m)Tc (N) heterocomplex LogP No. of Retention or run ^(99m)Tc complex time (min) Log k′ Stability 1[^(99m)Tc (N) (PNP3) (DTC)⁺] 8.8 0.6 Stable 2 [^(99m)Tc (N) (PNP3)(DMDC)⁺] 10.1 2.83 Stable 3 [^(99m)Tc (N) (PNP3) (DEDC)⁺] 14.2 2.91Stable 4 [^(99m)Tc (N) (PNP3) (DPDC)⁺] 22.8 3.51 Stable 5 [^(99m)Tc (N)(PNP3) (NOME)⁺] 10.3 2.84 Stable 6 [^(99m)Tc (N) (PNP3) (NOET)⁺] 15.82.79 Stable 7 [^(99m)Tc (N) (PNP3) (PROME)⁺] 14.0 3.28 Stable 8[^(99m)Tc (N) (PNP3) (BOET)⁺] 17.4 3.24 Stable 9 [^(99m)Tc (N) (PNP3)(POET)⁺] 13.6 2.88 Stable 10 [^(99m)Tc (N) (PNP3) (DPODC)⁺] 13.1 3.18Stable 11 [^(99m)Tc (N) (PNP3) (DBODC)⁺] 21.3 3.82 Stable Note 1) runNo. 1: HPLC conditions; mobile phase A: CH₃COONH₄ (0.01M, pH = 5) 10%,B: CH₃CN(THF 0.1%) 90%, C18, 0.5 mL/min Log P (partition coefficient) isshown. Note 2) run Nos 2 to 11: HPLC conditions; mobiule phase A:phosphate buffer (0.02M, pH = 7.4) 25%, B: CH₃OH 75%, C18, 1.0 mL/minLog k′ (partition ratio) is shown.

EXAMPLE 4 Measurement of Log k′ and Rf

Log k′o values, measured at various compositions of the mobile phase,were determind for the ^(99m)Tc(N) heterocomplexes obtained using PNP5or PNP6 as a bisphosphinoamine compound. The analysis of therelationship between Log k′o values and the mobile-phase compositionyielded extrapolated Log k′ values as a measure of the partitioningbetween the hydrophobic stationary phase and water. The Log k′ valueswere extrapolated from the linear part of the curve.

TLC chromatography was carried out on silica-gel plates and using themixture ethanol/chloroform/toluene/[NH₄][CH₃COO] (0.5 M) (5:3:3:0.5) asmobile phase. Activity was revealed using a Cyclone® instruments(Packard) equipped with a phosphor imaging screen and an OptiQuantsoftware package. HPLC analysis was performed on a Beckman System Goldinstrument equipped with a Programmable Solvent Module 126, a scanningdetector Module 166 and a radioisotope detector Module 170. A C18reversed-phase precolumn (Ultrasphere Beckman, 4.6×45 mm), a C18reversed-phase column (Ultrasphere Beckman, 4.6×250 mm) and a 100-μLloop were used. The mobile phase was methanol in various mixtures (%v/v) with a phosphate buffer (pH=7.4, 0.02M) at a flow rate of 1.0 mLmin⁻¹. Before injection, all solutions were purified using a C_(M)Sep-Pak cartridge. The elution time (to) of a non-retained component wasregarded as being equal to the elution time of sodium pertechnetate(2.77 min) The log k′ values at 0% organic solvent (Log k′o) wereextrapolated from the linear part of the curve Log k′=a+bC, where C isthe methanol concentration and Log k′=Log (tR-to)/to(tR=HPLC retentiontime, min). Results for the ^(99m)Tc(N) heterocomplexes are shown onTable 2.

TABLE 2 Log k′ and Rf of ^(99m)Tc (N) heterocomplex ^(99m)Tc (N)heterocomplex LOG k′ Rf PNP5•DBODC 3.69 0.65 PNP5•NOME 2.48 0.43PNP5•ISOET — 0.60 PNP5•BOET — 0.54 PNP6•DBODC — 0.80

EXAMPLE 5 Biodistribution of the ^(99m)Tc(N) Heterocomiplexes

The biodistribution was measured by using female Sprague-Dawley rats (SDrats) weighing 200 g to 250 g. Each of the ^(99m)Tc(N) heterocomplexespurified in the manner described above was diluted with phosphate buffer(0.1 M, pH=7.4) to obtain a final solution having an ethanol content of10%. After the SD rats were anesthetized with an intramuscular injectionof a mixture of ketamine (80 mg/kg) and xilazine (19 mg/kg), the jugularvein of each rat was surgically exposed and 100 μL (300 to 370 kBq) ofthe solution containing each ^(99m)Tc(N) heterocomplexes prepared in themanner described above was injected in the jugular vein. The rats (n=3)were sacrificed by cervical dislocation at different times postinjection. The blood was withdrawn from the heart through a syringe andcounted. It was assumed that the whole blood content was 6.5% of thetotal body weight. The organs were excised from the rats, washed withphysiological saline, weighed, and counted in a NaI well counter. Tables3 to 18 show the results of the biodistribution measurement.

For comparison, Tables 19 and 20 show the results, obtained in the samemanner as above, of measuring the biodistribution of (^(99m)Tc) (MIBI)and (^(99m)Tc) (Tf) which have been used as pharmaceuticals fordiagnostic imaging for blood flow in myocardium.

Tables 21 to 23 show data showing the variations with time of heartaccumulation, heart/lung ratios and heart/liver ratios for the^(99m)Tc(N) heterocomplexes of the present invention.

As can be seen from the data, the technetium-99m nitride heterocomplexesaccording to the present invention are markedly accumulated in heart andadrenal glands and their clearance from lungs and liver are rapid, sothat high heart/lung and heart/liver ratios are attained. Thus, thetechnetium-99m nitride heterocomplexes according to the presentinvention have been proved to be useful for radiodiagnostic imaging ofheart and adrenal glands.

TABLE 3 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (DTC)]⁺ (% ID/g)Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.68 ± 0.200.26 ± 0.10 0.16 ± 0.00 0.04 ± 0.00 0.03 ± 0.00 0.02 ± 0.01 0.01 ± 0.00Submaxillary glands 1.28 ± 0.42 1.48 ± 0.08 1.44 ± 0.07 1.36 ± 0.12 0.94± 0.22 1.29 ± 0.01 1.12 ± 0.12 Brain 0.11 ± 0.02 0.017 ± 0.004 0.010 ±0.001 0.009 ± 0.001 0.007 ± 0.000 0.007 ± 0.002 0.005 ± 0.001 Heart 1.87± 0.02 2.17 ± 0.02 2.58 ± 0.09 2.02 ± 0.10 1.67 ± 0.05 2.20 ± 0.10 2.23± 0.19 Lungs 1.27 ± 0.20 0.73 ± 0.10 0.62 ± 0.05 0.48 ± 0.07 0.38 ± 0.000.18 ± 0.04 0.27 ± 0.00 Liver 2.26 ± 0.36 3.46 ± 0.16 2.23 ± 0.50 0.77 ±0.22 0.60 ± 0.10 0.23 ± 0.03 0.24 ± 0.04 Spleen 0.93 ± 0.20 0.68 ± 0.050.55 ± 0.03 0.39 ± 0.06 0.28 ± 0.01 0.24 ± 0.04 0.16 ± 0.03 AdrenalGlands 1.71 ± 0.64 1.52 ± 0.11 1.08 ± 0.07 1.29 ± 0.13 0.76 ± 0.16 0.94± 0.08 0.39 ± 0.02 Kidneys 9.39 ± 1.29 8.57 ± 0.89 6.51 ± 1.08 4.44 ±0.69 3.64 ± 0.04 3.30 ± 0.06 3.03 ± 0.32 Intestine 2.99 ± 0.36 4.45 ±0.90 15.34 ± 0.89  12.25 ± 0.82  10.43 ± 0.23  9.94 ± 0.29 3.04 ± 0.48Muscle 0.16 ± 0.02 0.21 ± 0.00 0.18 ± 0.01 0.12 ± 0.03 0.18 ± 0.04 0.17± 0.01 0.13 ± 0.01

TABLE 4 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (DEDC)]⁺ (% ID/g)Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.42 ± 0.030.19 ± 0.01 0.06 ± 0.01 0.05 ± 0.01 0.02 ± 0.00 0.015 ± 0.001 0.010 ±0.000 Submaxillary glands 1.26 ± 0.32 1.24 ± 0.18 1.16 ± 0.32 1.05 ±0.13 0.99 ± 0.08 1.13 ± 0.12 1.66 ± 0.09 Brain 0.11 ± 0.03 0.02 ± 0.000.02 ± 0.00 0.010 ± 0.000 0.012 ± 0.005 0.012 ± 0.002 0.005 ± 0.001Heart 2.74 ± 0.10 2.55 ± 0.02 2.84 ± 0.00 2.90 ± 0.09 2.26 ± 0.20 2.50 ±0.04 2.85 ± 0.04 Lungs 1.69 ± 0.34 0.85 ± 0.05 0.92 ± 0.10 0.94 ± 0.010.59 ± 0.08 0.52 ± 0.03 0.51 ± 0.02 Liver 1.78 ± 0.23 3.69 ± 0.80 1.64 ±0.19 0.93 ± 0.05 0.34 ± 0.05 0.19 ± 0.01 0.14 ± 0.02 Spleen 2.26 ± 0.240.88 ± 0.10 0.19 ± 0.02 0.96 ± 0.02 0.64 ± 0.04 0.52 ± 0.09 0.36 ± 0.06Adrenal Glands 3.29 ± 0.62 2.54 ± 0.12 1.86 ± 0.02 3.34 ± 0.48 1.79 ±0.32 2.16 ± 0.62 3.46 ± 0.43 Kidneys 10.15 ± 0.66  11.21 ± 1.12  7.59 ±1.30 7.00 ± 0.40 4.64 ± 0.36 4.28 ± 0.15 4.28 ± 0.06 Intestine 4.48 ±1.44 4.25 ± 0.60 13.65 ± 2.55  13.34 ± 3.81  7.87 ± 3.81 6.26 ± 1.866.95 ± 3.71 Muscle 0.015 ± 0.04  0.16 ± 0.02 0.12 ± 0.03 0.13 ± 0.020.16 ± 0.04 0.18 ± 0.02 0.17 ± 0.02

TABLE 5 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (NOET)]⁺ (% ID/g)Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.26 ± 0.010.15 ± 0.02 0.05 ± 0.02 0.02 ± 0.00 0.03 ± 0.01 0.01 ± 0.00 0.01 ± 0.00Submaxillary glands 2.13 ± 0.16 1.10 ± 0.14 1.11 ± 0.16 1.34 ± 0.14 1.06± 0.21 1.39 ± 0.21 1.66 ± 0.35 Brain 0.10 ± 0.01 0.02 ± 0.01 0.02 ± 0.010.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 Heart 2.93 ± 0.02 2.87 ±0.14 2.86 ± 0.40 3.11 ± 0.77 2.97 ± 0.43 2.42 ± 0.19 2.78 ± 0.21 Lungs1.29 ± 0.20 0.82 ± 0.09 0.63 ± 0.02 0.57 ± 0.17 0.60 ± 0.03 0.38 ± 0.090.34 ± 0.06 Liver 1.56 ± 0.12 2.65 ± 0.17 1.36 ± 0.39 0.68 ± 0.23 0.54 ±0.08 0.18 ± 0.12 0.09 ± 0.02 Spleen 1.76 ± 0.36 1.44 ± 0.12 1.20 ± 0.210.72 ± 0.12 1.02 ± 0.31 0.40 ± 0.02 0.41 ± 0.06 Adrenal Glands 2.25 ±0.50 2.08 ± 0.58 2.07 ± 0.60 1.75 ± 0.32 1.87 ± 0.38 1.55 ± 0.12 1.82 ±0.70 Kidneys 10.0 ± 0.40 10.6 ± 1.08 6.11 ± 1.08 4.88 ± 1.02 5.54 ± 0.633.28 ± 0.47 3.77 ± 0.49 Intestine 3.92 ± 0.94 6.84 ± 0.70 7.15 ± 1.468.78 ± 3.90 11.03 ± 3.80  5.53 ± 2.84 5.22 ± 3.07 Muscle 0.20 ± 0.010.17 ± 0.03 0.11 ± 0.04 0.17 ± 0.04 0.12 ± 0.01 0.15 ± 0.04 0.16 ± 0.02

TABLE 6 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (DMDC)]⁺ (% ID/g)Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.73 ± 0.240.21 ± 0.04 0.05 ± 0.01 0.04 ± 0.01 0.03 ± 0.01 0.02 ± 0.00 0.01 ± 0.00Submaxillary glands 1.19 ± 0.38 1.50 ± 0.15 1.44 ± 0.12 1.73 ± 0.24 1.31± 0.14 1.50 ± 0.22 1.51 ± 0.10 Brain 0.16 ± 0.02 0.02 ± 0.01 0.02 ± 0.000.01 ± 0.00 0.01 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 Heart 2.55 ± 0.26 2.41 ±0.14 2.45 ± 0.23 2.39 ± 0.22 2.17 ± 0.07 2.55 ± 0.18 2.33 ± 0.26 Lungs1.17 ± 0.13 0.86 ± 0.11 0.54 ± 0.08 0.38 ± 0.03 0.33 ± 0.01 0.23 ± 0.010.18 ± 0.02 Liver 2.59 ± 0.96 3.48 ± 0.72 1.08 ± 0.24 0.71 ± 0.23 0.65 ±0.49 0.18 ± 0.03 0.09 ± 0.01 Spleen 1.37 ± 0.29 0.66 ± 0.16 0.38 ± 0.050.26 ± 0.01 0.21 ± 0.02 0.13 ± 0.02 0.07 ± 0.02 Adrenal Glands 1.21 ±0.25 1.14 ± 0.14 1.51 ± 0.29 1.00 ± 0.20 1.04 ± 0.25 1.09 ± 0.28 1.04 ±0.03 Kidneys 7.86 ± 1.48 9.71 ± 1.29 4.84 ± 1.19 3.85 ± 0.45 3.62 ± 0.732.96 ± 0.37 2.36 ± 0.89 Intestine 4.44 ± 0.57 3.71 ± 1.31 13.54 ± 3.02 12.96 ± 1.59  11.87 ± 3.34  8.22 ± 5.24 3.05 ± 0.99 Muscle 0.27 ± 0.110.20 ± 0.02 0.35 ± 0.19 0.27 ± 0.07 0.26 ± 0.06 0.28 ± 0.04 0.31 ± 0.05

TABLE 7 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (NOME)]⁺ (% ID/g)Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.64 ± 0.150.14 ± 0.01 0.04 ± 0.00 0.03 ± 0.00 0.03 ± 0.00 0.01 ± 0.00 0.01 ± 0.00Submaxillary glands 0.76 ± 0.01 0.76 ± 0.13 0.88 ± 0.15 1.00 ± 0.09 0.84± 0.04 0.80 ± 0.11 0.74 ± 0.14 Brain 0.16 ± 0.05 0.02 ± 0.00 0.01 ± 0.000.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 Heart 1.23 ± 0.09 1.16 ±0.06 1.13 ± 0.07 1.15 ± 0.08 1.33 ± 0.10 1.31 ± 0.05 1.16 ± 0.04 Lungs0.66 ± 0.03 0.36 ± 0.03 0.30 ± 0.02 0.26 ± 0.01 0.28 ± 0.01 0.21 ± 0.030.16 ± 0.02 Liver 1.24 ± 0.04 1.75 ± 0.16 0.76 ± 0.10 0.54 ± 0.03 0.30 ±0.02 0.12 ± 0.02 0.07 ± 0.01 Spleen 0.60 ± 0.02 0.31 ± 0.02 0.24 ± 0.010.17 ± 0.00 0.20 ± 0.01 0.14 ± 0.02 0.08 ± 0.02 Adrenal Glands 0.61 ±0.02 0.57 ± 0.16 0.55 ± 0.03 0.64 ± 0.08 0.54 ± 0.11 0.66 ± 0.23 0.66 ±0.06 Kidneys 0.258 ± 0.15  4.60 ± 0.34 2.26 ± 0.35 1.94 ± 0.35 2.23 ±0.06 1.93 ± 0.27 1.66 ± 0.23 Intestine 1.10 ± 0.09 2.52 ± 0.44 5.92 ±2.66 8.43 ± 0.67 6.52 ± 1.16 4.53 ± 1.21 3.86 ± 1.72 Muscle 0.11 ± 0.080.11 ± 0.00 0.16 ± 0.03 0.15 ± 0.01 0.14 ± 0.01 0.11 ± 0.01 0.12 ± 0.01

TABLE 8 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (DPDC)]⁺ (% ID/g)Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.74 ± 0.080.11 ± 0.03 0.03 ± 0.01 0.02 ± 0.01 0.02 ± 0.00 0.02 ± 0.00 0.01 ± 0.00Submaxillary glands 0.88 ± 0.20 0.70 ± 0.01 0.86 ± 0.14 0.93 ± 0.16 0.77± 0.06 0.72 ± 0.04 0.86 ± 0.18 Brain 0.08 ± 0.01 0.02 ± 0.01 0.02 ± 0.000.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.00 ± 0.00 Heart 2.50 ± 0.23 2.09 ±0.18 1.92 ± 0.28 1.76 ± 0.07 1.50 ± 0.06 1.74 ± 0.17 1.66 ± 0.16 Lungs0.83 ± 0.10 0.64 ± 0.11 0.44 ± 0.05 0.42 ± 0.05 0.28 ± 0.02 0.34 ± 0.020.24 ± 0.05 Liver 0.57 ± 0.10 1.70 ± 0.51 1.13 ± 0.28 0.72 ± 0.14 0.43 ±0.03 0.17 ± 0.05 0.07 ± 0.01 Spleen 0.97 ± 0.23 1.36 ± 0.20 1.27 ± 0.181.20 ± 0.16 0.78 ± 0.12 0.76 ± 0.18 0.56 ± 0.02 Adrenal Glands 2.94 ±0.88 1.97 ± 0.02 2.26 ± 0.41 2.38 ± 0.26 2.15 ± 0.41 2.21 ± 0.56 2.57 ±0.71 Kidneys 5.78 ± 1.97 6.19 ± 2.31 5.22 ± 2.39 5.62 ± 0.75 5.02 ± 1.343.93 ± 1.18 3.75 ± 0.24 Intestine 1.90 ± 0.48 2.68 ± 0.77 4.37 ± 2.135.06 ± 0.94 4.79 ± 2.32 7.68 ± 3.34 2.34 ± 1.44 Muscle 0.15 ± 0.05 0.11± 0.06 0.11 ± 0.03 0.11 ± 0.03 0.10 ± 0.02 0.10 ± 0.02 0.08 ± 0.02

TABLE 9 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (DPODC)]⁺ (%ID/g) Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 1.36 ±0.02 0.30 ± 0.09 0.21 ± 0.00 0.08 ± 0.02 0.04 ± 0.00 0.02 ± 0.01 0.01 ±0.00 Submaxillary glands 2.27 ± 0.20 1.22 ± 0.11 1.70 ± 0.60 1.38 ± 0.071.53 ± 0.17 1.33 ± 0.46 1.36 ± 0.14 Brain 0.20 ± 0.02 0.02 ± 0.00 0.01 ±0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 Heart 3.08 ± 0.312.06 ± 0.13 2.37 ± 0.33 2.49 ± 0.31 2.57 ± 0.06 2.26 ± 0.60 2.45 ± 0.41Lungs 1.45 ± 0.04 0.65 ± 0.06 0.67 ± 0.23 0.43 ± 0.05 0.41 ± 0.04 0.27 ±0.09 0.20 ± 0.04 Liver 3.48 ± 0.24 3.71 ± 0.36 3.49 ± 0.09 1.86 ± 0.471.30 ± 0.71 0.42 ± 0.23 0.16 ± 0.04 Spleen 1.23 ± 0.01 0.51 ± 0.04 0.57± 0.22 0.38 ± 0.04 0.37 ± 0.00 0.18 ± 0.10 0.14 ± 0.03 Adrenal Glands1.65 ± 0.22 0.98 ± 0.12 1.49 ± 0.82 1.46 ± 0.15 1.31 ± 0.19 1.17 ± 0.171.14 ± 0.15 Kidneys 6.36 ± 0.13 8.21 ± 0.62 6.82 ± 3.62 5.63 ± 2.05 4.88± 0.56 3.44 ± 0.76 3.43 ± 0.38 Intestine 3.25 ± 0.60 4.30 ± 1.74 4.36 ±2.28 14.47 ± 4.75  11.78 ± 1.78  11.05 ± 5.05  16.10 ± 2.10  Muscle 0.27± 0.02 0.25 ± 0.04 0.29 ± 0.08 0.39 ± 0.12 0.32 ± 0.08 0.27 ± 0.04 0.36± 0.12

TABLE 10 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (DBODC)]⁺ (%ID/g) Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.55 ±0.32 0.11 ± 0.01 0.03 ± 0.00 0.02 ± 0.01 0.02 ± 0.00 0.01 ± 0.00 0.01 ±0.00 Submaxillary glands 1.25 ± 0.47 1.27 ± 0.05 1.42 ± 0.24 1.32 ± 0.211.49 ± 0.22 1.29 ± 0.28 1.59 ± 0.19 Brain 0.23 ± 0.04 0.03 ± 0.00 0.02 ±0.00 0.02 ± 0.01 0.02 ± 0.02 0.01 ± 0.00 0.01 ± 0.00 Heart 3.57 ± 0.143.42 ± 0.19 3.65 ± 0.56 3.32 ± 0.18 3.27 ± 0.36 3.27 ± 0.62 3.00 ± 0.42Lungs 1.54 ± 0.03 1.01 ± 0.49 0.77 ± 0.10 0.84 ± 0.06 0.69 ± 0.12 0.34 ±0.11 0.27 ± 0.05 Liver 1.46 ± 0.05 1.72 ± 0.26 1.43 ± 0.47 0.87 ± 0.520.42 ± 0.01 0.16 ± 0.05 0.12 ± 0.03 Spleen 1.84 ± 0.49 2.00 ± 0.07 1.28± 0.12 0.92 ± 0.10 0.95 ± 0.02 0.42 ± 0.11 0.21 ± 0.03 Adrenal Glands2.68 ± 0.44 2.87 ± 1.00 2.30 ± 0.73 2.69 ± 0.37 2.94 ± 0.18 2.17 ± 0.352.53 ± 0.27 Kidneys 10.40 ± 2.16  11.57 ± 2.37  6.74 ± 0.63 6.12 ± 0.115.67 ± 0.39 4.24 ± 0.53 3.48 ± 0.61 Intestine 2.43 ± 0.49 7.42 ± 1.0312.11 ± 2.92  13.03 ± 3.19  13.41 ± 4.62  4.39 ± 2.86 7.03 ± 2.61 Muscle0.23 ± 0.04 0.23 ± 0.01 0.23 ± 0.07 0.13 ± 0.02 0.24 ± 0.08 0.17 ± 0.010.36 ± 0.15

TABLE 11 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (BOET)]⁺ (%ID/g) Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.40 ±0.15 0.16 ± 0.02 0.06 ± 0.02 0.03 ± 0.00 0.02 ± 0.01 0.02 ± 0.00 0.01 ±0.00 Submaxillary glands 1.32 ± 0.45 1.26 ± 0.19 1.14 ± 0.14 1.08 ± 0.131.27 ± 0.35 1.34 ± 0.29 1.11 ± 0.18 Brain 0.21 ± 0.05 0.03 ± 0.00 0.02 ±0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.00 ± 0.00 Heart 3.24 ± 0.783.14 ± 0.08 2.88 ± 0.33 3.09 ± 0.19 2.89 ± 0.18 2.84 ± 0.06 3.00 ± 0.24Lungs 0.98 ± 0.27 0.98 ± 0.23 0.69 ± 0.11 0.61 ± 0.15 0.44 ± 0.06 0.40 ±0.07 0.22 ± 0.05 Liver 1.87 ± 0.19 2.03 ± 0.24 1.22 ± 0.28 0.72 ± 0.140.45 ± 0.07 0.26 ± 0.03 0.12 ± 0.03 Spleen 2.14 ± 0.68 1.53 ± 0.17 1.14± 0.14 0.84 ± 0.06 0.62 ± 0.08 0.46 ± 0.07 0.40 ± 0.02 Adrenal Glands2.59 ± 0.73 2.77 ± 0.49 2.56 ± 0.20 2.34 ± 0.81 2.35 ± 0.24 2.04 ± 0.352.42 ± 0.22 Kidneys 10.12 ± 1.80  12.13 ± 1.80  7.92 ± 1.01 5.22 ± 2.095.66 ± 0.46 3.66 ± 0.50 3.81 ± 0.10 Intestine 3.45 ± 0.46 4.68 ± 1.288.61 ± 2.43 12.25 ± 2.29  9.18 ± 6.12 8.78 ± 1.91 9.42 ± 0.81 Muscle0.19 ± 0.04 0.20 ± 0.04 0.16 ± 0.07 0.15 ± 0.02 0.26 ± 0.04 0.21 ± 0.020.19 ± 0.05

TABLE 12 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (POET)]⁺ (%ID/g) Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.40 ±0.20 0.13 ± 0.02 0.04 ± 0.00 0.03 ± 0.00 0.03 ± 0.01 0.01 ± 0.00 0.01 ±0.00 Submaxillary glands 1.01 ± 0.32 1.19 ± 0.03 1.30 ± 0.12 1.21 ± 0.131.28 ± 0.19 1.27 ± 0.07 1.19 ± 0.04 Brain 0.20 ± 0.07 0.02 ± 0.00 0.01 ±0.00 0.02 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 0.01 ± 0.00 Heart 2.21 ± 0.232.65 ± 0.26 2.49 ± 0.09 2.45 ± 0.24 2.31 ± 0.09 2.37 ± 0.18 2.41 ± 0.17Lungs 0.85 ± 0.29 0.67 ± 0.08 0.55 ± 0.03 0.47 ± 0.06 0.42 ± 0.02 0.34 ±0.06 0.22 ± 0.02 Liver 1.70 ± 0.29 2.39 ± 0.41 1.74 ± 0.22 0.86 ± 0.290.44 ± 0.09 0.18 ± 0.05 0.09 ± 0.02 Spleen 1.08 ± 0.36 0.96 ± 0.12 0.65± 0.05 0.53 ± 0.03 0.46 ± 0.07 0.30 ± 0.06 0.15 ± 0.01 Adrenal Glands1.62 ± 0.52 1.79 ± 0.16 1.79 ± 0.39 1.79 ± 0.73 1.76 ± 0.23 1.99 ± 0.391.82 ± 0.25 Kidneys 7.36 ± 1.08 9.94 ± 1.22 5.40 ± 0.27 5.27 ± 0.85 4.29± 0.61 3.41 ± 0.71 2.45 ± 0.29 Intestine 2.57 ± 0.57 4.05 ± 0.70 5.11 ±1.86 8.87 ± 3.00 13.51 ± 3.87  9.88 ± 1.81 7.02 ± 1.78 Muscle 0.19 ±0.05 0.17 ± 0.02 0.16 ± 0.04 0.21 ± 0.11 0.19 ± 0.08 0.17 ± 0.03 0.26 ±0.04

TABLE 13 Biodistribution in rats of [^(99m)Tc(N) (PNP3) (PROME)]⁺ (%ID/g) Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.59 ±0.07 0.15 ± 0.02 0.07 ± 0.05 0.03 ± 0.00 0.04 ± 0.02 0.02 ± 0.00 0.02 ±0.01 Submaxillary glands 1.70 ± 0.35 1.51 ± 0.03 1.44 ± 0.15 1.41 ± 0.111.46 ± 0.52 1.46 ± 0.22 1.59 ± 0.31 Brain 0.17 ± 0.06 0.02 ± 0.00 0.01 ±0.00 0.01 ± 0.00 0.01 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 Heart 2.62 ± 0.062.76 ± 0.47 2.33 ± 0.33 2.46 ± 0.15 2.62 ± 0.35 2.41 ± 0.32 2.71 ± 0.23Lungs 1.09 ± 0.17 0.84 ± 0.08 0.56 ± 0.05 0.47 ± 0.02 0.31 ± 0.07 0.21 ±0.05 0.18 ± 0.00 Liver 1.65 ± 0.11 2.04 ± 0.24 1.53 ± 0.54 0.68 ± 0.050.41 ± 0.14 0.12 ± 0.02 0.10 ± 0.01 Spleen 1.32 ± 0.07 0.99 ± 0.07 0.71± 0.04 0.51 ± 0.01 0.31 ± 0.06 0.15 ± 0.04 0.12 ± 0.01 Adrenal Glands1.81 ± 0.06 2.72 ± 0.51 2.08 ± 0.49 2.03 ± 0.45 1.45 ± 0.06 1.88 ± 0.251.61 ± 0.28 Kidneys 7.99 ± 0.11 10.31 ± 1.05  6.01 ± 1.55 4.14 ± 0.063.10 ± 1.83 2.62 ± 0.50 2.71 ± 0.57 Intestine 2.84 ± 0.46 5.52 ± 1.168.15 ± 1.02 7.22 ± 0.56 10.76 ± 2.35  6.66 ± 1.16 7.85 ± 1.25 Muscle0.17 ± 0.04 0.18 ± 0.00 0.19 ± 0.02 0.19 ± 0.04 0.23 ± 0.07 0.19 ± 0.050.18 ± 0.03

TABLE 14 Biodistribution in rats of the complex [^(99m)Tc(N) (PNP5)(DBODC)]⁺ (% dose/g) Organ 0 min 2 min 10 min 20 min 30 min 60 min 120min. Blood 6.65 ±  0.11 ± 0.03 ± 0.02 ± 0.02 ± 0.01 ± 0.01 ± 0.50  0.020.01 0.00 0.00 0.00 0.00 Submax. 0.16 ±  1.77 ± 1.79 ± 1.57 ± 1.88 ±1.84 ± 2.09 ± glands 0.02  0.18 0.23 0.23 0.50 0.10 0.14 Brain 0.45 ± 0.03 ± 0.01 ± 0.01 ± 0.01 ± 0.01 ± 0.00 ± 0.09  0.00 0.00 0.01 0.000.00 0.00 Heart 5.01 ±  3.94 ± 3.69 ± 3.63 ± 3.73 ± 3.76 ± 3.31 ± 0.16 0.32 0.29 0.46 0.48 0.39 0.06 Lungs 6.58 ±  0.99 ± 0.88 ± 0.57 ± 0.64 ±0.46 ± 0.25 ± 1.09  0.36 0.03 0.08 0.13 0.07 0.01 Liver 0.82 ±  2.66 ±1.61 ± 0.96 ± 0.72 ± 0.20 ± 0.10 ± 0.09  0.88 0.21 0.09 0.06 0.05 0.03Spleen 1.75 ±  2.68 ± 1.79 ± 1.41 ± 0.92 ± 0.41 ± 0.21 ± 0.21  0.45 0.310.12 0.34 0.30 0.06 Adrenal 2.87 ±  3.95 ± 3.73 ± 3.00 ± 3.36 ± 4.17 ±3.44 ± glands 0.37  0.76 1.03 0.55 0.05 0.48 0.88 Kidneys 3.71 ± 14.69 ±9.16 ± 6.58 ± 6.70 ± 5.73 ± 3.48 ± 2.38  2.30 1.08 0.80 0.98 0.55 0.14Intestine 1.71 ±  7.97 ± 9.04 ± 9.63 ± 6.70 ± 6.52 ± 6.57 ± 1.33  0.941.71 1.60 0.71 7.65 5.38 Muscle 0.09 ±  0.20 ± 0.21 ± 0.17 ± 0.19 ± 0.21± 0.23 ± 0.11  0.04 0.05 0.02 0.04 0.03 0.06

TABLE 15 Biodistribution in rats of the complex [^(99m)Tc(N) (PNP5)(NOME)]⁺ (% dose/g) Organ 0 min 2 min 10 min 20 min 30 min 60 min 120min. Blood 2.18 ± 0.15 ± 0.07 ± 0.03 ± 0.03 ±  0.02 ±  0.01 ± 0.74 0.010.01 0.00 0.01  0.00  0.00 Submax. 1.41 ± 2.34 ± 2.16 ± 1.78 ± 1.99 ± 1.88 ±  1.95 ± glands 0.50 0.09 0.09 0.18 0.18  0.47  0.19 Brain 0.08 ±0.01 ± 0.01 ± 0.01 ± 0.01 ±  0.01 ±  0.00 ± 0.02 0.00 0.00 0.00 0.00 0.00  0.00 Heart 2.74 ± 2.14 ± 2.08 ± 2.08 ± 2.11 ±  2.05 ±  2.25 ±2.14 0.34 0.32 0.10 0.25  0.31  0.18 Lungs 1.07 ± 0.57 ± 0.45 ± 0.46 ±0.37 ±  0.29 ±  0.23 ± 0.21 0.07 0.04 0.07 0.04  0.07  0.01 Liver 2.99 ±3.63 ± 2.77 ± 1.59 ± 0.93 ±  0.33 ±  0.21 ± 1.15 0.69 0.51 0.36 0.12 0.05  0.05 Spleen 1.03 ± 0.88 ± 0.59 ± 0.48 ± 0.31 ±  0.17 ±  0.16 ±0.31 0.15 0.05 0.03 0.02  0.02  0.03 Adrenal 1.65 ± 1.60 ± 1.80 ± 1.74 ±1.29 ±  1.30 ±  1.65 ± glands 0.23 0.33 0.29 0.31 0.38  0.38  0.11Kidneys 8.00 ± 8.50 ± 5.09 ± 4.17 ± 3.92 ±  3.02 ±  2.98 ± 0.62 1.920.69 0.58 0.51  0.40  0.16 Intestine 2.28 ± 5.65 ± 8.42 ± 15.58 ± 14.61± 10.97 ± 14.39 ± 0.31 1.51 2.25 8.20 7.86  2.29  6.43 Muscle 0.25 ±0.18 ± 0.23 ± 0.30 ± 0.22 ±  0.22 ±  0.18 ± 0.03 0.04 0.08 0.02 0.05 0.04  0.05

TABLE 16 Biodistribution in rats of the complex [^(99m)Tc(N) (PNP5)(ISOET)]⁺ (% dose/g) Organ 10 min 2 min 10 min 20 min 30 min 60 min 120min. Blood 0.93 ± 0.14 ± 0.04 ± 0.02 ± 0.02 ± 0.02 ± 0.01 ± 0.20 0.020.01 0.00 0.00 0.00 0.00 Submax. 0.92 ± 0.95 ± 1.40 ± 1.85 ± 1.51 ± 1.79± 1.38 ± glands 0.34 0.21 0.31 0.52 0.07 0.17 0.21 Brain 0.10 ± 0.02 ±0.02 ± 0.01 ± 0.01 ± 0.00 ± 0.01 ± 0.02 0.00 0.01 0.01 0.00 0.00 0.01Heart 3.35 ± 2.33 ± 2.91 ± 2.86 ± 2.47 ± 2.74 ± 2.44 ± 0.51 0.17 0.360.07 0.49 0.19 0.05 Lungs 2.44 ± 0.74 ± 0.73 ± 0.50 ± 0.45 ± 0.35 ± 0.22± 1.06 0.16 0.29 0.09 0.04 0.03 0.03 Liver 0.95 ± 2.79 ± 1.54 ± 1.09 ±1.06 ± 0.43 ± 0.23 ± 0.54 0.14 0.10 0.12 0.14 0.15 0.01 Spleen 1.16 ±1.11 ± 1.28 ± 1.20 ± 0.35 ± 0.73 ± 0.41 ± 0.20 0.14 0.16 0.23 0.08 0.180.13 Adrenal 2.22 ± 2.24 ± 2.70 ± 2.70 ± 2.72 ± 2.23 ± 2.98 ± glands0.66 0.15 0.42 0.56 0.35 0.42 0.45 Kidneys 5.40 ± 7.19 ± 5.98 ± 5.31 ±5.28 ± 5.12 ± 4.50 ± 1.18 0.40 1.35 0.25 0.41 0.35 0.39 Intestine 3.70 ±3.68 ± 7.12 ± 7.44 ± 8.36 ± 8.29 ± 8.00 ± 1.58 0.67 2.04 2.27 0.32 0.610.75 Muscle 0.13 ± 0.16 ± 0.22 ± 0.20 ± 0.13 ± 0.15 ± 0.19 ± 0.01 0.040.00 0.01 0.03 0.08 0.05

TABLE 17 Biodistribution in rats of the complex [^(99m)Tc(N) (PNP5)(BOET)]⁺ (% dose/g) Organ 0 min 2 min 10 min 20 min 30 min 60 min 120min. Blood 0.38 ± 0.10 ± 0.03 ± 0.02 ±  0.02 ± 0.01 ± 0.01 ± 0.15 0.050.01 0.00  0.00 0.00 0.00 Submax. 1.28 ± 1.21 ± 1.15 ± 0.94 ±  1.38 ±1.24 ± 1.17 ± glands 0.25 0.21 0.04 0.13  0.17 0.12 0.14 Brain 0.17 ±0.02 ± 0.01 ± 0.01 ±  0.01 ± 0.00 ± 0.00 ± 0.05 0.00 0.00 0.00  0.000.00 0.00 Heart 3.59 ± 2.89 ± 2.68 ± 2.63 ±  2.56 ± 2.69 ± 2.67 ± 0.780.28 0.21 0.21  0.26 0.19 0.45 Lungs 0.84 ± 0.61 ± 0.54 ± 0.53 ±  0.36 ±0.40 ± 0.20 ± 0.27 0.21 0.12 0.03  0.03 0.06 0.04 Liver 3.87 ± 2.44 ±1.45 ± 1.02 ±  1.11 ± 0.47 ± 0.22 ± 0.19 0.65 0.13 0.27  0.49 0.09 0.06Spleen 1.25 ± 1.42 ± 1.09 ± 0.93 ±  0.70 ± 0.55 ± 0.30 ± 0.48 0.09 0.110.11  0.05 0.02 0.11 Adrenal 2.59 ± 2.31 ± 2.87 ± 2.55 ±  2.69 ± 2.54 ±2.84 ± glands 0.73 0.17 0.16 0.32  0.41 0.23 1.00 Kidneys 7.59 ± 8.87 ±7.62 ± 6.94 ±  5.34 ± 5.28 ± 5.06 ± 1.24 1.24 2.32 0.18  0.28 0.58 1.49Intestine 4.11 ± 5.63 ± 6.14 ± 8.46 ± 12.02 ± 8.70 ± 5.89 ± 0.46 0.932.07 1.55  0.69 4.94 4.35 Muscle 0.10 ± 0.09 ± 0.19 ± 0.10 ±  0.16 ±0.14 ± 0.12 ± 0.04 0.01 0.06 0.01  0.12 0.01 0.04

TABLE 18 Biodistribution in rats of the complex [^(99m)Tc(N) (PNP5)(OBODC)]⁺ (% dose/g) Organ 0 min  2 min 10 min 20 min 30 min 60 min 120min. Blood 1.42 ±  0.17 ± 0.06 ± 0.03 ± 0.05 ± 0.02 ± 0.02 ± 0.76  0.010.02 0.01 0.03 0.00 0.01 Submax. 1.17 ±  1.26 ± 1.27 ± 1.03 ± 1.08 ±1.30 ± 1.36 ± glands 0.21  0.33 0.20 0.27 0.24 0.19 0.12 Brain 0.18 ± 0.03 ± 0.03 ± 0.03 ± 0.02 ± 0.01 ± 0.01 ± 0.07  0.00 0.00 0.01 0.010.00 0.00 Heart 2.26 ± 1.241 ± 1.39 ± 1.18 ± 1.05 ± 1.10 ± 1.29 ± 0.82 0.14 0.30 0.18 0.19 0.11 0.16 Lungs 3.87 ±  1.25 ± 1.10 ± 0.80 ± 0.60 ±0.48 ± 0.33 ± 1.82  0.42 0.21 0.16 0.08 0.02 0.05 Liver 3.59 ±  5.94 ±7.71 ± 6.55 ± 4.66 ± 3.55 ± 2.55 ± 1.82  1.80 1.05 1.88 0.56 0.64 0.69Spleen 1.68 ±  3.85 ± 4.00 ± 3.13 ± 2.43 ± 2.64 ± 2.02 ± 0.35  0.26 0.900.78 0.23 0.29 0.50 Adrenal 2.60 ±  3.49 ± 4.48 ± 3.19 ± 3.08 ± 3.49 ±3.47 ± glands 0.10  1.04 1.75 0.15 0.21 0.16 0.83 Kidneys 5.56 ±  9.57 ±9.80 ± 8.18 ± 7.52 ± 6.60 ± 8.83 ± 1.51  1.93 2.06 1.84 1.16 1.29 1.19Intestine 2.91 ±  3.54 ± 6.21 ± 8.54 ± 7.75 ± 8.37 ± 9.70 ± 0.73  0.750.16 1.88 2.71 3.09 2.51 Muscle 0.06 ±  0.17 ± 0.16 ± 0.09 ± 0.11 ± 0.12± 0.14 ± 0.07  0.07 0.05 0.02 0.01 0.00 0.01

TABLE 19 Biodistribution in rats of (^(99m)Tc) (MIBI)⁺ complex (% ID/g)Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.34 ± 0.070.11 ± 0.01 0.07 ± 0.01 0.05 ± 0.01 0.05 ± 0.01 0.03 ± 0.00 0.02 ± 0.00Submaxillary glands 1.43 ± 0.41 1.01 ± 0.23 1.12 ± 0.12 1.07 ± 0.04 1.08± 0.09 1.17 ± 0.05 1.19 ± 0.05 Brain 0.26 ± 0.01 0.04 ± 0.01 0.05 ± 0.010.04 ± 0.01 0.04 ± 0.02 0.04 ± 0.00 0.03 ± 0.00 Heart 3.56 ± 0.22 3.25 ±0.17 3.37 ± 0.45 3.16 ± 0.22 3.70 ± 0.04 3.18 ± 0.17 3.04 ± 0.14 Lungs1.65 ± 0.08 1.18 ± 0.13 1.36 ± 0.31 0.99 ± 0.11 0.72 ± 0.01 0.47 ± 0.240.47 ± 0.06 Liver 1.36 ± 0.12 1.88 ± 0.08 2.21 ± 0.27 1.98 ± 0.60 1.37 ±0.22 1.57 ± 0.11 1.02 ± 0.23 Spleen 2.65 ± 0.26 2.76 ± 0.66 3.16 ± 0.622.11 ± 0.18 2.89 ± 0.29 1.88 ± 0.15 1.23 ± 0.18 Adrenal Glands 2.80 ±0.17 1.60 ± 0.01 3.28 ± 0.39 3.05 ± 0.04 3.49 ± 0.67 3.50 ± 0.60 2.43 ±0.13 Kidneys 9.23 ± 0.62 10.12 ± 0.15  11.45 ± 1.62  8.14 ± 1.30 6.46 ±0.11 4.42 ± 0.11 3.49 ± 0.05 Intestine 3.55 ± 0.37 3.71 ± 0.01 5.40 ±0.33 4.90 ± 0.23 5.42 ± 0.05 6.49 ± 1.43 4.15 ± 1.02 Muscle 0.24 ± 0.040.14 ± 0.00 0.18 ± 0.01 0.15 ± 0.05 0.17 ± 0.05 0.18 ± 0.01 0.28 ± 0.05

TABLE 20 Biodistribution in rats of (^(99m)Tc) (Tf)⁺ complex (% ID/g)Organ 0 min 2 min 10 min 20 min 30 min 60 min 120 min Blood 0.48 ± 0.050.22 ± 0.01 0.05 ± 0.00 0.04 ± 0.00 0.03 ± 0.00 0.04 ± 0.01 0.02 ± 0.00Submaxillary glands 2.06 ± 0.57 1.23 ± 0.09 1.10 ± 0.13 1.27 ± 0.17 0.92± 0.00 1.53 ± 0.13 1.13 ± 0.16 Brain 0.24 ± 0.11 0.04 ± 0.00 0.03 ± 0.010.02 ± 0.00 0.02 ± 0.00 0.02 ± 0.00 0.01 ± 0.00 Heart 2.79 ± 0.42 3.15 ±0.28 2.57 ± 0.35 2.74 ± 0.13 2.45 ± 0.14 2.79 ± 0.52 2.65 ± 0.07 Lungs1.03 ± 0.22 0.85 ± 0.08 0.77 ± 0.10 0.67 ± 0.10 0.67 ± 0.08 0.51 ± 0.050.35 ± 0.01 Liver 2.09 ± 0.30 2.52 ± 0.64 1.90 ± 0.45 1.26 ± 0.29 1.28 ±0.12 0.71 ± 0.06 0.58 ± 0.15 Spleen 1.73 ± 0.03 2.08 ± 0.45 1.40 ± 0.181.14 ± 0.24 1.45 ± 0.04 1.11 ± 0.10 0.97 ± 0.02 Adrenal Glands 1.75 ±0.09 2.38 ± 0.12 2.28 ± 0.38 2.05 ± 0.25 1.81 ± 0.18 3.08 ± 0.01 2.66 ±0.18 Kidneys 4.63 ± 0.68 9.73 ± 2.17 5.52 ± 1.07 5.74 ± 0.72 4.36 ± 0.144.05 ± 0.50 3.12 ± 0.50 Intestine 2.64 ± 0.91 5.22 ± 0.69 7.70 ± 1.417.33 ± 1.11 10.52 ± 1.70  8.88 ± 1.94 7.02 ± 0.74 Muscle 0.16 ± 0.040.29 ± 0.05 0.21 ± 0.05 0.25 ± 0.01 0.18 ± 0.05 0.25 ± 0.04 0.28 ± 0.12

TABLE 21 Heart accumulation in rats of [^(99m)Tc(N)](PNP3, PNP5 or PNP6)(XY)⁺ (% ID/g) ^(99m−)Tc complex 0 min 2 min 10 min 20 min 30 min 60 min120 min [^(99m−)Tc(N) (PNP3) (DTC) ⁺] 1.87 ± 0.30 2.17 ± 0.02 2.58 ±0.09 2.02 ± 0.09 1.67 ± 0.05 2.20 ± 0.09 2.23 ± 0.19 [^(99m−)Tc(N)(PNP3) (DMDC)⁺] 2.55 ± 0.26 2.41 ± 0.14 2.45 ± 0.23 2.39 ± 0.22 2.17 ±0.07 2.55 ± 0.18 2.33 ± 0.26 [^(99m−)Tc(N) (PNP3) (DEDC)⁺] 2.74 ± 0.102.55 ± 0.02 2.85 ± 0.00 2.90 ± 0.09 2.26 ± 0.20 2.50 ± 0.05 2.85 ± 0.05[^(99m−)Tc(N) (PNP3) (DPDC)⁺] 2.50 ± 0.23 2.09 ± 0.18 1.92 ± 0.28 1.76 ±0.07 1.50 ± 0.06 1.74 ± 0.17 1.66 ± 0.16 [^(99m−)Tc(N) (PNP3) (NOME)⁺]1.23 ± 0.09 1.16 ± 0.06 1.13 ± 0.07 1.15 ± 0.08 1.33 ± 0.10 1.31 ± 0.051.16 ± 0.04 [^(99m−)Tc(N) (PNP3) (NOET)⁺] 2.93 ± 0.02 2.87 ± 0.14 2.86 ±0.40 3.11 ± 0.77 2.97 ± 0.43 2.42 ± 0.19 2.78 ± 0.21 [^(99m−)Tc(N)(PNP3) (PRONE)⁺] 2.21 ± 0.23 2.65 ± 0.26 2.49 ± 0.09 2.45 ± 0.24 2.31 ±0.09 2.37 ± 0.18 2.41 ± 0.17 [^(99m−)Tc(N) (PNP3) (BOET)⁺] 3.24 ± 0.783.14 ± 0.08 2.88 ± 0.33 3.09 ± 0.19 2.89 ± 0.18 2.84 ± 0.04 3.00 ± 0.24[^(99m−)Tc(N) (PNP3) (POET)⁺] 2.62 ± 0.06 2.76 ± 0.47 2.33 ± 0.33 2.46 ±0.15 2.62 ± 0.35 2.41 ± 0.32 2.71 ± 0.23 [^(99m−)Tc(N) (PNP3) (DPODC)⁺]3.08 ± 0.31 2.06 ± 0.13 2.37 ± 0.33 2.49 ± 0.31 2.57 ± 0.06 2.26 ± 0.062.45 ± 0.41 [^(99m−)Tc(N) (PNP3) (DBODC)⁺] 3.57 ± 0.14 3.42 ± 0.19 3.65± 0.56 3.32 ± 0.18 3.27 ± 0.36 3.27 ± 0.62 3.00 ± 0.42 [^(99m−)Tc(N)(PNP5) (DBODC)⁺] 5.01 ± 0.16 3.94 ± 0.32 3.69 ± 0.29 3.63 ± 0.46 3.73 ±0.48 3.76 ± 0.39 3.31 ± 0.06 [^(99m−)Tc(N) (PNP5) (NOME)⁺] 2.74 ± 2.142.14 ± 0.34 2.08 ± 0.32 2.08 ± 0.10 2.11 ± 0.25 2.05 ± 0.31 2.25 ± 0.18[^(99m−)Tc(N) (PNP5) (ISOET)⁺] 3.35 ± 0.51 2.33 ± 0.17 2.91 ± 0.36 2.86± 0.07 2.47 ± 0.49 2.74 ± 0.19 2.44 ± 0.05 [^(99m−)Tc(N) (PNP5) (BOET)⁺]3.59 ± 0.78 2.89 ± 0.28 2.68 ± 0.21 2.63 ± 0.21 2.56 ± 0.26 2.69 ± 0.192.67 ± 0.45 [^(99m−)Tc(N) (PNP6) (DBODC)⁺] 2.26 ± 0.82 1.24 ± 0.14 1.39± 0.30 1.18 ± 0.18 1.05 ± 0.19 1.10 ± 0.11 1.29 ± 0.16 (^(99m−)Tc)(MIBI)⁺ 3.56 ± 0.22 3.25 ± 0.17 3.37 ± 0.45 3.16 ± 0.22 3.70 ± 0.04 3.18± 0.17 3.04 ± 0.14 (^(99m−)Tc) (Tf)⁺ 2.79 ± 0.42 3.15 ± 0.28 2.57 ± 0.352.74 ± 0.13 2.45 ± 0.14 2.79 ± 0.52 2.65 ± 0.07

TABLE 22 Heart/lung ratio in biodistribution of [^(99m)Tc(N)](PNP3, PNP5or PNP6) (XY)⁺ in rats ^(99m−)Tc complex 0 min 2 min 10 min 20 min 30min 60 min 120 min [^(99m−)Tc(N) (PNP3) (DTC)^(+]) 1.47 2.97 4.13 4.224.41 12.51 8.25 [^(99m−)Tc(N) (PNP3) (DMDC)⁺] 2.18 2.80 4.54 6.29 6.5811.09 12.94 [^(99m−)Tc(N) (PNP3) (DEDC)⁺] 1.62 3.01 3.08 2.99 3.86 4.705.61 [^(99m−)Tc(N) (PNP3) (DPDC)⁺] 3.01 3.27 4.36 4.19 5.36 5.11 6.91[^(99m−)Tc(N) (PNP3) (NOME)⁺] 1.86 3.22 3.77 4.42 4.75 6.24 7.25[^(99m−)Tc(N) (PNP3) (NOET)⁺] 2.27 3.28 4.55 5.42 4.98 6.31 8.27[^(99m−)Tc(N) (PNP3) (PROME)⁺] 2.60 3.96 4.53 5.21 5.50 6.97 10.95[^(99m−)Tc(N) (PNP3) (BOET)⁺] 3.31 3.20 4.17 5.07 6.57 7.10 13.64[^(99m−)Tc(N) (PNP3) (POET)⁺] 2.40 3.29 4.16 5.23 8.45 11.48 15.06[^(99m−)Tc(N) (PNP3) (DPODC)⁺] 2.12 3.17 3.54 5.79 6.27 8.37 12.25[^(99m−)Tc(N) (PNP3) (DBODC)⁺] 2.32 3.39 4.74 3.95 4.74 9.60 11.10[^(99m)Tc(N) (PNP5) (DBODC)⁺] 0.76 3.98 4.19 6.37 5.83 8.17 13.24[^(99m)Tc(N) (PNP5) (NOME)⁺] 2.56 3.75 4.62 4.52 5.70 7.07 9.78[^(99m)Tc(N) (PNP5) (ISOET)⁺] 1.37 3.15 3.99 5.72 5.49 7.83 11.09[^(99m)Tc(N) (PNP5) (BOET)⁺] 4.27 4.74 4.96 4.96 7.11 6.73 13.35[^(99m)Tc(N) (PNP6) (DBODC)⁺] 0.58 0.99 1.26 1.48 1.75 2.29 3.91(^(99m−)Tc) (MIBI)⁺ 2.16 2.75 2.44 3.19 5.14 6.77 6.47 (^(99m−)Tc) (Tf)⁺2.71 3.71 3.34 4.09 3.66 5.47 7.57

TABLE 23 Heart/liver ratio in biodistribution of [^(99m)Tc(N)] (PNP3,PNP5 or PNP6) (XY)⁺ in rats ^(99m−)Tc complex 0 min 2 min 10 min 20 min30 min 60 min 120 min [^(99m−)Tc(N) (PNP3) (DTC)⁺] 0.83 0.63 1.16 2.612.79 9.56 9.44 [^(99m−)Tc(N) (PNP3) (DMDC)⁺] 0.98 0.69 2.27 3.37 3.3414.17 25.89 [^(99m−)Tc(N) (PNP3) (DEDC)⁺] 1.53 0.69 1.73 3.13 6.59 13.3719.81 [^(99m−)Tc(N) (PNP3) (DPDC)⁺] 4.39 1.23 1.71 2.44 3.49 10.24 23.71[^(99m−)Tc(N) (PNP3) (NOME)⁺] 0.99 0.66 1.49 2.13 4.43 10.92 16.57[^(99m−)Tc(N) (PNP3) (NOET)⁺] 1.88 1.08 2.11 4.55 5.52 13.31 30.21[^(99m−)Tc(N) (PNP3) (PROME)⁺] 1.31 1.11 1.43 2.85 5.25 13.17 26.78[^(99m−)Tc(N) (PNP3) (BOET)⁺] 1.73 1.55 2.36 4.29 6.42 10.92 25.01[^(99m−)Tc(N) (PNP3) (POET)⁺] 1.59 1.35 1.52 3.62 6.39 20.08 27.01[^(99m−)Tc(N) (PNP3) (DPODC)⁺] 0.89 0.56 0.68 1.34 1.98 5.38 15.31[^(99m−)Tc(N) (PNP3) (DBODC)⁺] 2.45 1.99 2.55 3.82 7.79 20.44 25.01[^(99m)Tc(N) (PNP5) (DBODC)⁺] 6.11 1.48 2.29 3.78 5.18 18.8 33.1[^(99m)Tc(N) (PNP5) (NOME)⁺] 0.92 0.58 0.75 1.33 2.26 6.21 10.71[^(99m)Tc(N) (PNP5) (ISOET)⁺] 3.53 0.83 1.90 2.62 2.33 6.37 10.61[^(99m)Tc(N) (PNP5) (BOET)⁺] 0.93 1.18 1.84 2.58 2.30 5.72 12.14[^(99m)Tc(N) (PNP6) (DBODC)⁺] 0.63 0.21 0.18 0.18 0.23 0.31 0.51(^(99m−)Tc) (MIBI)⁺ 2.62 1.73 1.52 1.61 2.71 2.03 2.98 (^(99m−)Tc) (Tf)⁺1.33 1.25 1.35 2.17 1.91 3.93 4.57

EXAMPLE 6 Production of a Kit for Preparing a Pharmaceutical forDiagnostic Imaging

(1) The following compositions are placed in a vial 1 and a vial 2,respectively, and freeze-dried:

Run 1 Run 2 Vial 1 SDH   5 mg   5 mg EDTA   5 mg   5 mg SnC1₂•2H₂O 0.1mg 0.1 mg Phosphate buffer (0.1M)   1 mL   1 mL Vial 2 PNP3 1.5 mg 3.5mg DBODC   3 mg 3.5 mg γ-Cylodextrin 7.5 mg 3.5 mg

(2) From the freeze-dried compositions described above, a pharmaceuticalfor diagnostic imaging containing a technetium-99m nitride heterocomplexcan be obtained as follows.

In the vial 1 was placed 1 to 2 mL of Na[^(99m)TcO₄] eluted from a⁹⁹Mo—^(99m)Tc generator, and the vial 1 is sufficiently shaken and thenallowed to stand for 15 minutes. 1.5 mL of physiological saline isplaced in the vial 2 to dissolve the contents, and 1 mL of the resultingsolution is placed in the vial 1. After thoroughly mixing, the resultingmixture was heated at about 100° C. for 15 minutes and then allowed tocool at room temperature.

Above both preparations showed no effect on the final yield and theamount of the various substances is not critical.

INDUSTRIAL APPLICABILITY

The present inventive radiopharmaceutical for diagnostic imagingcontaining a technetium-99m nitride heterocomplex as an activeingredient is markedly accumulated in heart and adrenal glands with highheart/lung and heart/liver ratios, and hence has been proved to beuseful as radiopharmaceutical for diagnostic imaging of heart andadrenal glands.

1. A radiopharmaceutical for diagnostic imaging, comprising an ion oftechnetium-99m nitride heterocomplex, represented by following formula(1):[^(99m)Tc(N)(PNP)(XY)]⁺  (1) wherein ^(99m)Tc is a metastable nuclearisomer of technetium-99m; N is a nitrogen atom bonded to ^(99m)Tc; PNPis a bisphosphinoamine ligand coordinated with ^(99m)Tc and XY is abidentate ligand coordinated with ^(99m)Tc, wherein thebisphosphinoamine ligand isbis(di(methoxypropyl)phosphinoethyl)ethoxyethylamine and the bidentateligand is selected from the group consisting ofN-ethoxyethyl-N-isopropyl dithiocarbamate, N-ethoxyethyl-N-ethyldithiocarbamate, and -N-diethoxyethyl dithiocarbamate.
 2. A kit forpreparing a radiopharmaceutical for diagnostic imaging according toclaim 1, comprising: a first container containing a first compositioncomprising a nitride nitrogen donor and a reducing agent, and a secondcontainer containing a second composition comprising a bisphosphinoaminecompound PNP and a bidentate ligand XY; wherein the bisphosphinoaminecompound PNP is bis(di(methoxypropyl)phosphinoethyl)ethoxyethylamine andthe bidentate ligand XY is selected from the group consisting ofN-ethoxyethyl-N-isopropyl dithiocarbamate, N-ethoxyethyl-N-ethyldithiocarbamate; and N-diethoxyethyl dithiocarbamate.
 3. A kit forpreparing a radiopharmaceutical for diagnostic imaging according toclaim 2, wherein the contents of the first and second containers havebeen freeze-dried.
 4. A kit for preparing a radiopharmaceutical fordiagnostic imaging according to claim 2, wherein the nitride nitrogendonor is selected from the group consisting of dithiocarbazic acid,dithiocarbazic acid derivatives, hydrazine and.
 5. A kit for preparing aradiopharmaceutical for diagnostic imaging according to claim 2, whereinthe reducing agent is selected from the group consisting of stannouschloride, sodium hydrogensulfite, sodium borohydride, tertiaryphosphines and tris-(m-sulfonatophenyl)phosphine.